Background: Studies assessing knowledge, attitude and practice (KAP) of coronavirus disease 2019 (COVID-19) are essential to support interventions and to resolve misconceptions about the disease. Objective: To assess KAP, measure the impact of COVID-19 on participants' lives, determine stigmatization, and identify intentions toward COVID-19 vaccination. Methods: A cross-sectional study was conducted between December 2020 and February 2021 in Upper Egypt. Participants were recruited using social media (Facebook and WhatsApp) and data were collected using online questionnaire. Results: Among 512 participants completed the survey, 59.6% were aged 20–39 years, and 55.3% were women. Approximately 61.5% of the participants had a good knowledge level, 60.2% had a positive attitude, and 52.9% had a good practice score. Social media was the main (63.3%) source of information. Vaccine intention was poor in 42.0% of the participants, and the majority considered COVID-19 a source of stigma. Significant predictors of good knowledge were employment in the medical profession, aged 20–39 years and higher level of education (OR: 5.9, 3.02, and 3.1, respectively). Significant predictors of positive attitude were employment in the medical profession, marriage, and male gender (OR: 2.4, 2.0 and 2.03, respectively). Significant predictors of good practice were marriage, urban residency and female gender (OR: 2.9, 1.6 and 1.5, respectively). Conclusions: Social media and a lack of organized sources of knowledge have adversely impacted the public's COVID-19-related KAP in Upper Egypt. Well-organized community outreach programs led by health authorities are essential to raise public awareness, reduce COVID-19-related stigma, and increase vaccine uptake.